Dose escalation of tamoxifen in patients with low endoxifen level: Evidence for therapeutic drug monitoring - The TADE study

Peter Fox, Rosemary L. Balleine, Clara Lee, Bo Gao, Bavanthi Balakrishnar, Alexander M. Menzies, Shang Heng Yeap, Sayed Sahanawaz Ali, Val Gebski, Pamela Provan, Sally Coulter, Christopher Liddle, Rina Hui, Richard Kefford, Jodi Lynch, Mark Wong, Nicholas Wilcken, Howard Gurney

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes.

LanguageEnglish
Pages3164-3171
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number13
DOIs
Publication statusPublished - 1 Jul 2016

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Drug Monitoring
Tamoxifen
Hot Flashes
Cytochrome P-450 CYP2D6
Genotype
Breast Neoplasms
4-hydroxy-N-desmethyltamoxifen
Research Design

Cite this

Fox, Peter ; Balleine, Rosemary L. ; Lee, Clara ; Gao, Bo ; Balakrishnar, Bavanthi ; Menzies, Alexander M. ; Yeap, Shang Heng ; Ali, Sayed Sahanawaz ; Gebski, Val ; Provan, Pamela ; Coulter, Sally ; Liddle, Christopher ; Hui, Rina ; Kefford, Richard ; Lynch, Jodi ; Wong, Mark ; Wilcken, Nicholas ; Gurney, Howard. / Dose escalation of tamoxifen in patients with low endoxifen level : Evidence for therapeutic drug monitoring - The TADE study. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 13. pp. 3164-3171.
@article{b970521e922f45e38fc00c476ab01287,
title = "Dose escalation of tamoxifen in patients with low endoxifen level: Evidence for therapeutic drug monitoring - The TADE study",
abstract = "Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24{\%} had endoxifen levels below 15 nmol/L and this reduced to 6{\%} following dose escalation. In over 50{\%} of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63{\%} of PM patients, and 58{\%} of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes.",
author = "Peter Fox and Balleine, {Rosemary L.} and Clara Lee and Bo Gao and Bavanthi Balakrishnar and Menzies, {Alexander M.} and Yeap, {Shang Heng} and Ali, {Sayed Sahanawaz} and Val Gebski and Pamela Provan and Sally Coulter and Christopher Liddle and Rina Hui and Richard Kefford and Jodi Lynch and Mark Wong and Nicholas Wilcken and Howard Gurney",
year = "2016",
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doi = "10.1158/1078-0432.CCR-15-1470",
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Fox, P, Balleine, RL, Lee, C, Gao, B, Balakrishnar, B, Menzies, AM, Yeap, SH, Ali, SS, Gebski, V, Provan, P, Coulter, S, Liddle, C, Hui, R, Kefford, R, Lynch, J, Wong, M, Wilcken, N & Gurney, H 2016, 'Dose escalation of tamoxifen in patients with low endoxifen level: Evidence for therapeutic drug monitoring - The TADE study', Clinical Cancer Research, vol. 22, no. 13, pp. 3164-3171. https://doi.org/10.1158/1078-0432.CCR-15-1470

Dose escalation of tamoxifen in patients with low endoxifen level : Evidence for therapeutic drug monitoring - The TADE study. / Fox, Peter; Balleine, Rosemary L.; Lee, Clara; Gao, Bo; Balakrishnar, Bavanthi; Menzies, Alexander M.; Yeap, Shang Heng; Ali, Sayed Sahanawaz; Gebski, Val; Provan, Pamela; Coulter, Sally; Liddle, Christopher; Hui, Rina; Kefford, Richard; Lynch, Jodi; Wong, Mark; Wilcken, Nicholas; Gurney, Howard.

In: Clinical Cancer Research, Vol. 22, No. 13, 01.07.2016, p. 3164-3171.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dose escalation of tamoxifen in patients with low endoxifen level

T2 - Clinical Cancer Research

AU - Fox, Peter

AU - Balleine, Rosemary L.

AU - Lee, Clara

AU - Gao, Bo

AU - Balakrishnar, Bavanthi

AU - Menzies, Alexander M.

AU - Yeap, Shang Heng

AU - Ali, Sayed Sahanawaz

AU - Gebski, Val

AU - Provan, Pamela

AU - Coulter, Sally

AU - Liddle, Christopher

AU - Hui, Rina

AU - Kefford, Richard

AU - Lynch, Jodi

AU - Wong, Mark

AU - Wilcken, Nicholas

AU - Gurney, Howard

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes.

AB - Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes.

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JF - Clinical Cancer Research

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